Department of Pharmacology and Toxicology, University of Utah, Salt Lake, UT 84112, USA.
Department of Medicinal Chemistry, University of Utah, Salt Lake, UT 84112, USA.
Mar Drugs. 2021 Jan 18;19(1):41. doi: 10.3390/md19010041.
Patients diagnosed with basal-like breast cancer suffer from poor prognosis and limited treatment options. There is an urgent need to identify new targets that can benefit patients with basal-like and claudin-low (BL-CL) breast cancers. We screened fractions from our Marine Invertebrate Compound Library (MICL) to identify compounds that specifically target BL-CL breast cancers. We identified a previously unreported trisulfated sterol, i.e., topsentinol L trisulfate (TLT), which exhibited increased efficacy against BL-CL breast cancers relative to luminal/HER2+ breast cancer. Biochemical investigation of the effects of TLT on BL-CL cell lines revealed its ability to inhibit activation of AMP-activated protein kinase (AMPK) and checkpoint kinase 1 (CHK1) and to promote activation of p38. The importance of targeting AMPK and CHK1 in BL-CL cell lines was validated by treating a panel of breast cancer cell lines with known small molecule inhibitors of AMPK (dorsomorphin) and CHK1 (Ly2603618) and recording the increased effectiveness against BL-CL breast cancers as compared with luminal/HER2+ breast cancer. Finally, we generated a drug response gene-expression signature and projected it against a human tumor panel of 12 different cancer types to identify other cancer types sensitive to the compound. The TLT sensitivity gene-expression signature identified breast and bladder cancer as the most sensitive to TLT, while glioblastoma multiforme was the least sensitive.
被诊断患有基底样乳腺癌的患者预后较差，治疗选择有限。迫切需要确定新的靶点，以使基底样和 Claudin-low（BL-CL）乳腺癌患者受益。我们从我们的海洋无脊椎动物化合物库（MICL）中筛选了各个馏分，以鉴定专门针对 BL-CL 乳腺癌的化合物。我们发现了一种以前未报道的三硫酸甾醇，即 topsentinol L 三硫酸盐（TLT），它对 BL-CL 乳腺癌的疗效相对于腔型/HER2+乳腺癌有所提高。TLT 对 BL-CL 细胞系作用的生化研究表明，它能够抑制 AMP 激活蛋白激酶（AMPK）和检查点激酶 1（CHK1）的激活，并促进 p38 的激活。通过用已知的 AMPK（dorsomorphin）和 CHK1（Ly2603618）小分子抑制剂处理一组乳腺癌细胞系，并记录其对 BL-CL 乳腺癌的有效性相对于腔型/HER2+乳腺癌的增加，验证了在 BL-CL 细胞系中靶向 AMPK 和 CHK1 的重要性。最后，我们生成了一个药物反应基因表达特征，并将其投射到 12 种不同癌症类型的人类肿瘤面板上，以确定对该化合物敏感的其他癌症类型。TLT 敏感性基因表达特征确定了乳腺癌和膀胱癌对 TLT 最敏感，而多形性胶质母细胞瘤最不敏感。
